The treatment of clinically localized prostate cancer remains controversial. Surgical extirpation of prostatic carcinoma (radical prostatectomy) has proven to be effective therapy if cancer is pathologically confined to the prostate. However, pre-surgical clinical staging frequently underestimates the pathologic extent of disease leading to a high rate of positive surgical margins or extraprostatic tumor discovered after surgery. This has raised concerns on the appropriateness of radical prostatectomy in a significant group of clinically localized tumors. This research proposal is focused on an innovative therapeutic strategy designed to improve current treatment results of patients with clinically localized prostate cancer. Specifically, the strategy consists of a combined modality approach employing primary hormonal manipulation followed by surgical resection of clinically localized prostatic carcinoma. The specific aims of our proposal are: (1)To examine the benefit of pre-operative hormonal manipulation in the pathologic downstaging of clinically localized prostate cancer. This will be accomplished through a prospective randomized trial comparing final pathologic stage of disease between the study group receiving 3 months of Zoladex and Flutamide treatment followed by radical prostatectomy versus the control group undergoing radical prostatectomy alone. (2)To prospectively determine the value of biological tumor parameters in predicting the response of prostatic cancer to hormonal manipulation and final pathologic stage. The biological parameters to be studied are: steroid hormone receptor expression (immunohistochemical analysis of androgen, estrogen and progesterone receptors), tumor proliferative activity and DNA content (flowcytometric determination of DNA ploidy, S and G2-M phases, Ki-67 immunoflowcytometry), and differentiation and therapy- associated phenotypes (PSA, PAP, neuroendocrine markers and MDR). These assessments will be performed on pre-therapy prostatic biopsies and post- therapy radical prostatectomy specimens. (3)To characterize the biologic changes occurring in human prostatic tumors associated with androgen withdrawal with respect to steroid hormone receptor expression, tumor proliferative activity and differentiation and therapy-associated phenotypes. These studies are aimed at (1) identifying the changes in specific biologic characteristics of prostatic tumors with respect to hormonal manipulation and (2) characteristics of the sub- population of malignant cells that are able to survive following complete androgen ablation. This will provide valuable information regarding the biology of androgen-independent prostate cancer.